Paradoxical Psoriasis and Worsening Spondylitis Due to Secukinumab in a Patient With Ankylosing Spondylitis: A Case Report and Literature Review

Axial spondyloarthritis (axSpA) is an autoimmune disease primarily affecting the axial skeleton, with associated extra-musculoskeletal manifestations. Treatment strategies targeting cytokines tumor necrosis factor-alpha (TNF-α) and interleukin 17 (IL-17) have proven effective. However, paradoxical reactions, including paradoxical psoriasis and arthritis, have been reported in axSpA patients receiving TNF-α inhibitors. IL-17 inhibitors have been used as an alternative treatment option, but paradoxical reactions have also been rarely observed. This case report presents a 45-year-old man with axSpA who responded to infliximab for six years before discontinuing it due to secondary failure. After the washout period of infliximab, he was started on secukinumab but developed paradoxical psoriasis and worsening of inflammatory back pain after receiving the second loading dose which necessitated replacing it with upadacitinib. Complete resolution of paradoxical psoriasis and significant improvement in his back pain after three months ensued. This case contributes to understanding the complex dynamics in treating axSpA and managing paradoxical reactions.


Introduction
Axial spondyloarthritis (axSpA) is a chronic idiopathic inflammatory disease that primarily affects the axial skeleton and is classified into non-radiographic axSpA and radiographic axSpA (ankylosing spondylitis).Patients may also develop enthesitis, peripheral arthritis, and extra-musculoskeletal manifestations such as uveitis, psoriasis, and inflammatory bowel disease (IBD).This condition can cause significant disability due to ankylosis and loss of spinal mobility and work absenteeism [1].The 2022 Assessment of Spondyloarthritis International Society (ASAS)-European Alliance of Associations for Rheumatology (EULAR) recommendations for treating axSpA include non-pharmacological and pharmacological interventions, including interleukin 17 (IL-17) inhibitors, secukinumab, and ixekizumab [2].
With the wide use of biologics in the management of autoimmune diseases, paradoxical reactions (PRs), including paradoxical psoriasis (PP) and paradoxical arthritis, have been reported in the literature, particularly with tumor necrosis factor (TNF) inhibitors [3].PRs are unexpected and contrary responses to a drug where the intended therapeutic effect is not achieved and new or worsening symptoms occur.These reactions are considered paradoxical because they oppose the expected outcome based on the drug's mechanism of action or established therapeutic indications [4].
Our case report aims to present a unique case of PP and worsening inflammatory back pain due to IL-17 inhibitor, secukinumab, in a patient with axSpA.We also describe a review of the literature and summarize the clinical characteristics, management approach, and treatment outcomes of the published cases.

Case Presentation
A 45-year-old man of Egyptian descent presented with a history of obesity, hypertension, smoking, hyperlipidemia, and a previously treated left deep venous thrombosis (provoked by a traumatic fracture of the left leg and complicated by pulmonary embolism in 2017).He had a long-standing history of typical inflammatory back pain since the age of 18.At the end of 2016, he saw a rheumatologist when X-rays of the lumbosacral spine and sacroiliac joints (SIJs) showed lumbar syndesmophytes and bilateral grade 3 sacroiliitis (Figure 1).He was diagnosed with ankylosing spondylitis (AS) and fulfilled the modified New York criteria for AS.He had no personal or family history of peripheral arthritis, dactylitis, uveitis, psoriasis, or IBD.Due to the failure of many non-steroidal anti-inflammatory drugs, he was started on infliximab (Remicade) 5 mg/kg (500 mg) in April 2016.Methotrexate 10 mg orally weekly was added from 2016 to November 2022 as a concomitant therapy with infliximab (500 mg every eight weeks) in an attempt to reduce the formation of human anti-chimeric antibodies.His back pain improved.
On October 24th, 2022, he presented to our rheumatology clinic for a second opinion.He complained of recurrent severe lower back pain that affected his daily living and work.He reported a two-hour morning stiffness.He denied any trauma or infection.His other home medications included amlodipine-perindopril, rosuvastatin, and pantoprazole.On physical examination, his body mass index was 33.5 kg/m 2 , his blood pressure was 158/100 mmHg, and his heart rate was 80 beats/minute.The cervical range of motion was normal, while the occiput-to-wall distance was wide (7 cm), and chest expansion was normal (7 cm).The modified Schober test indicated restricted lumbar flexion at 1 cm, and lumbar lateral flexion was restricted bilaterally (7 cm).No joint swelling was observed.His blood tests revealed elevated C-reactive protein (CRP) of 12.4 mg/L (normal range: ≤5), negative anti-nuclear antibody, negative rheumatoid factor, negative hepatitis B and C serology, and a positive human leukocyte antigen B27.
On November 21st, 2022, due to persistent back pain, he returned to his primary rheumatologist and received his last infliximab infusion.His back pain did not improve afterward.On February 8th, 2023, he took the fifth dose of secukinumab, and after a week, he complained of worsening back pain.On March 8th, 2023, his spondylitis disease activity was high (very high ASDAS 5.0, high BASDAI score 8.6, high CRP 12.9 mg/L).His palmoplantar pustular psoriasis worsened significantly, and new plaque psoriasis on his right elbow and left knee developed (Figure 2, Panels b, c), despite using topical therapy and taking secukinumab.Again, he reported no triggering factors for the rash, such as stress, trauma, new drugs (except secukinumab), or infections.He was prescribed naproxen 500 mg twice daily for his back pain.During a multidisciplinary meeting between rheumatology and dermatology, it was agreed to continue topical therapy and replace secukinumab with JAK inhibitor, upadacitinib 15 mg daily, starting on March 10th, 2023.The goal was to treat both conditions, axSpA and PP.He also stopped smoking.
After one month of starting upadacitinib, the patient reported significant improvement in his back pain and significant resolution of his psoriasis.He became independent in his daily living.His CRP decreased to 7.3 mg/L.He was referred to physiotherapy to optimize his back mobility and was continued on naproxen.His psoriasis completely resolved after three months of taking upadacitinib (Figure 2, Panels d, e).He sustained improvement in back pain without skin symptoms for nine months.

Discussion
PRs can complicate treatment plans, leading to suboptimal or inadequate therapeutic responses to primary autoimmune disease.PRs may also result in the discontinuation or alteration of medications, necessitating further adjustments and potentially limiting treatment options [5].
A multi-center Turkish study recruited 8,192 patients, including 2,867 with RA and 5,316 with SpA.Out of 136 patients (1.66%) who experienced PRs, most were due to TNF inhibitors, with only one (0.7%) patient on secukinumab.Among those with PRs, 60% had them from their first biologic drug.The median time between PR onset and starting biologic treatment was 12 months.PP types included pustular (60.3%) and palmoplantar (30.9%).Switching to another biological drug was common among patients with PPs (73.2%).Progression of PPs occurred in only 5.2% of patients who switched to another TNF inhibitor.Interestingly, the study also noted a significantly higher number of smokers in patients with SpA [6].
A literature review was performed to search for English-language articles using PubMed, Web of Science, and Google Scholar databases.Search terms included "secukinumab," "paradox," "psoriasis," "psoriatic," "ankylosing spondylitis," and "spondyloarthritis."No time limits were applied.In addition, the available references were manually searched and reviewed to capture all potential cases.
We identified 18 cases with PP after secukinumab.Only five cases had spondyloarthritis.Only two out of the 18 cases were published in rheumatology journals, while the rest were published in dermatology journals.Table 1 shows a detailed description of the cases, while Table 2 summarizes the findings.PP is relatively common in patients taking TNF blockers, particularly infliximab [22].Interestingly, our patient's presentation resembles a published case (number 15 on the table) where the patient with spondyloarthritis had self-limited PP induced by etanercept, which was discontinued 10 years before starting secukinumab [18].However, our patient continued receiving infliximab for six years before its discontinuation due to secondary failure.It should be noted that the median half-life of infliximab ranges from 7.7 to 9.5 days, and the washout period is 29 days [23,24].Therefore, it is highly unlikely that infliximab triggered the PP that started after 60 days of the last infusion, coinciding with the second loading dose of secukinumab.In our case, the PP started as new palmoplantar pustular psoriasis and progressed into plaque psoriasis affecting other areas of the skin, in addition to worsening spondylitis disease activity measures, including high CRP levels.Furthermore, this is the first case reporting PP related to secukinumab and resolved with JAK inhibitor, upadacitinib.
Our case highlights that PPs and arthritis are not only specific adverse events to TNF-α inhibitors but also possible adverse events of any biological drug interfering with the immune system.While the exact pathophysiology of induced PPs is not fully understood, several mechanisms have been reported.First, it is suggested that plasmacytoid dendritic cells may increase the production of interferon-gamma, leading to enhanced T-cell activity.Second, a decrease in T-regulatory cells and an imbalance in immune reactions may contribute to the development of PPs.Furthermore, the dysregulation of cytokines, particularly the IL-17 pathway, is considered crucial in the development of PRs induced by secukinumab [3].Understanding the underlying mechanisms and risk factors associated with PRs can help guide treatment decisions.
Based on the literature review, management of PRs depends on their severity, primary underlying disease, and alternative treatment.The primary goals remain controlling the primary disease and treating the PR.
Options to be considered for managing PRs include continuation of the biologic drug if the PR is mild, topical treatment and/or ultraviolet phototherapy for mild psoriasis, the addition of conventional synthetic DMARDs (e.g., glucocorticosteroids, methotrexate), and replacement of the offending drug with another class of immunomodulatory drugs such as TNF inhibitors, IL-17 inhibitors, IL12-23 inhibitor, or JAK inhibitors.Switching within the same class carries a risk of recurrence and, therefore, is best avoided [22,25].Further research with a large number of patients may shed some light on the best management strategies for such cases.

Conclusions
TNF-α inhibitors and IL-17 inhibitors have proven to be effective drugs for axSpA.While they are generally well tolerated, increasing cases associated with PRs have been reported, mostly associated with TNF inhibitors.PP and arthritis are very rare with secukinumab.Our axSpA case demonstrates developing de novo PP and worsening spondylitis after being treated with an IL-17 inhibitor, secukinumab.Switching to a different class of immunomodulators, such as JAK inhibitors, is a reasonable therapeutic option with success, as experienced by our patient.Close monitoring for PRs, prompt recognition, and appropriate management are essential in optimizing therapeutic outcomes and minimizing the burden of these rare adverse events in patients with axSpA.Further research is needed to understand the underlying mechanisms and develop strategies to manage these complications in axSpA patients effectively.

7 FIGURE 1 :
FIGURE 1: X-rays of the lumbosacral spine (a) anteroposterior and (b) lateral view showing sacroiliitis grade 3 bilaterally (black arrows) and lumbar syndesmophytes (white arrows) confirming the diagnosis of ankylosing spondylitis.

FIGURE 2 :
FIGURE 2: Image (a) shows pustular psoriasis on the palm on January 20th, 2023, after receiving the second loading dose of secukinumab.On March 8th, 2023, image (b) shows plaque psoriasis on the left knee, and image (c) shows dried-up pustules on the palms, leaving behind fringes of desquamation after one week of receiving the fifth loading dose of secukinumab.Images (d and c) show complete resolution of psoriasis on the hands and left knee after three months of upadacitinib.

TABLE 2 : Summary of published paradoxical psoriasis cases secondary to secukinumab.
To summarize the published case reports, secukinumab can worsen axial symptoms and arthritis in cases with spondyloarthritis.PP is very rare with IL-17 inhibitor therapy, secukinumab, and occurs mostly in patients who have been exposed to TNF inhibitors.The mean duration of secukinumab use before PP is 19 weeks.Most patients had a new (de novo) morphologic type of PP.In most published cases, secukinumab was replaced with one or more new biologic DMARDs.Partial or complete resolution of symptoms is expected after approximately 10 months.